1. Sestrin2 drives ER-phagy in response to protein misfolding.
- Author
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De Leonibus C, Maddaluno M, Ferriero R, Besio R, Cinque L, Lim PJ, Palma A, De Cegli R, Gagliotta S, Montefusco S, Iavazzo M, Rohrbach M, Giunta C, Polishchuk E, Medina DL, Di Bernardo D, Forlino A, Piccolo P, and Settembre C
- Subjects
- Animals, Humans, Mice, Signal Transduction, Membrane Proteins metabolism, Membrane Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins genetics, Nuclear Proteins metabolism, Nuclear Proteins genetics, Lysosomes metabolism, Endoplasmic Reticulum Stress, Sestrins metabolism, Sestrins genetics, Phosphorylation, Proteostasis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Endoplasmic Reticulum metabolism, Protein Folding, Mechanistic Target of Rapamycin Complex 1 metabolism, X-Box Binding Protein 1 metabolism, X-Box Binding Protein 1 genetics
- Abstract
Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation. The mechanisms initiating ER-phagy in response to ER proteostasis defects are not well understood. By studying mouse primary cells and patient samples as a model of ER storage disorders (ERSDs), we show that accumulation of faulty products within the ER triggers a response involving SESTRIN2, a nutrient sensor controlling mTORC1 signaling. SESTRIN2 induction by XBP1 inhibits mTORC1's phosphorylation of TFEB/TFE3, allowing these transcription factors to enter the nucleus and upregulate the ER-phagy receptor FAM134B along with lysosomal genes. This response promotes ER-phagy of misfolded proteins via FAM134B-Calnexin complex. Pharmacological induction of FAM134B improves clearance of misfolded proteins in ERSDs. Our study identifies the interplay between nutrient signaling and ER quality control, suggesting therapeutic strategies for ERSDs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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